Cannabinoids are compounds derived from the cannabis sativa plant which is commonly known as marijuana. The most active chemical compound of the naturally ocurring cannabinoids is tetrahydrocannabinol (THC), particularly (-)-.DELTA..sup.9 -THC. This compound was isolated and identified in the 1960's and since that time there has been an ever increasing scientific investigation of the effects and pharmacology of the cannabinols. However, prior to discovery of THC, the effects and pharmacology of marijuana use have been known for several thousand years. Both the uses and abuses of marijuana are recorded from the earliest human records. Marijuana based medicants have been known for centuries and have been a mainstay of many folk, herbal remedies.
Among the many beneficial pharmacological properties attributed to marijuana are: analgesia, lowering blood and intra-ocular pressure, and anti-emetic activity in both mammals and man. Indeed, currently, there is much debate over whether marijuana use should be legalized in certain cases, such as its use in cancer patients for ameliorating the nausea induced by chemotherapy or to lower intra-ocular pressure in glaucoma patients. After the elucidation of THC, several synthetic compounds were discovered and have been used clinically for the treatment of cancer patients, among these are: Nabilone, Nabortate and Levonantrodol. However, although these drugs are useful, they have to a greater or lesser extent some of the negative pharmacologic properties of THC and thus, are limited in their general use.
As marijuana's beneficial effects have been long known, so to its negative effects have been well documented. Notable in the negative pharmacology associated with marijuana (and later shown to be associated with THC) are: psychological distortions of perception, loss of short-term memory, loss of motor coordination, sedation, and euphoria. Long term use of marijuana is considered by many to lead to addiction. Throughout the long history of marijuana its use and abuse have been intertwined.
Until the 1980's, the mechanism by which the cannabinols, most specifically THC, acted on the central nervous system was obscure. With the advent of very potent, radiolabelled, synthetic THC agonists (CP 55,940, HU210, and HU211), the search for the molecular basis of THC pharmacology began to be elucidated.
In 1988, it was determined that there was a specific receptor which bound .DELTA..sup.9 THC as well as the other synthetic agonists. Using radio autography, the cannabinol receptor was found to be localized in the hippocampus area of the rat brain (see: Herkenham, M., Ann. NY Acad. Sci., 645: p. 19-32 (1992) and references therein). (For a review of this chronology, see: Mechoulam, R., et al., CNS Drugs, 2(4), p. 255-260 (1994)). Subsequently, it was discovered that there was another, distinct receptor which appears to be primarily located in the peripheral tissues, especially in the immune system (see: Lynn, A. B. and Herkenham, M., J. Pharm. and Exp. Ther., 268(3), p. 1612-1623 (1994)). Both receptors have been purified, amino acid sequenced, cloned, and expressed in experimental cell lines. The two receptors which bind both the cannabinoids and their synthetic agonists have been designated as: CB-1, the receptor located in the central nervous system, and CB-2, the receptor found in peripheral tissues. It is generally agreed that much of the cannabinoid pharmacology, associated with its central nervous system effects and which is most germane to this invention, is directly related to the action of the CB-1 receptor. Synthetic and natural compounds which are agonists of the CB-1 receptor, demonstrate the expected experimental and human pharmacology, while closely related compounds which bind poorly to CB-1 do not. (For a review of these findings, see: Mechoulam, R., et al., Biochem. Pharm., 48(8), p. 1537-1544 (1994)).
In 1992, it was discovered that the endogenous ligand for the CB-1 receptor is anandamide, N-ethanolamine amide of arachidonic acid (see: Devane, W. A., et al., Science, 258, p. 1946-1949. (1992)). The discovery of this new neurotransmitter has initiated an intense investigation into the regulation and pharmacology of anandamide. Preliminary results indicate that animals treated with exogenous anandamide demonstrate behavior similar to those treated with cannabinoids. Because of the parallelism of cannabinoid and anandamide pharmacology and the area of the location in the brain of the CB-1 receptor, there is a growing body of evidence that anandamide is a key regulator of functions such as sensory perception, cognition, memory, pain perception, and mood modulation. Since it is very clear in humans what the agonism of the CB-1 receptor does with cannabinoids, it would seem reasonable by the same extrapolation to predict the likely pharmacology of antagonists of the CB-1 receptor would possess.
Therefore, in patients suffering from loss of sensory perception, cognition, and mood changes such as lethargy and depression, conditions which are often associated with the use of marijuana, there is a strong implication that a controlling factor exacerbating these events would be an inappropriately high or unregulated control of anandamide - CB-1 interaction. An anandamide - CB-1 antagontist would be useful in conditions where patients exhibit these symptoms.
There are two reports in the art of cannabinol receptor partial agonists or antagonists which are not either anandamide or cannabinoid analogs. The first of these compounds, an aminoalkylindole, a partial agonist, (see FIG. 1) is revealed in Pacheco, M., et al., J. Pharmacol. Exp. Ther., 257, p. 170-183 (1991) and Compton, D. R., et al., J. Pharmacol. Exp. Ther., 263, p. 1118-1126 (1992). The antagonist, a halo-aryl pyrazole (SR 141716A) (see FIG. 2), was revealed in a patent application EP 0576357A1. The CB-1 antagonist, SR141716A, has been shown to block the actions of both cannabinoids and anandamide in in vivo and in vitro models (see: Rinaldi-Carmons, M., et al., FEBS Letters, 350, p. 240-244 (1994)). ##STR1##